The present invention relates to a process for producing an aryl vinyl sulfone solution, methods of transportation and storage of an aryl vinyl sulfone as a solution, and use thereof.
Aryl vinyl sulfones are useful compounds as intermediates of drugs or other products. The organic layers containing crude aryl vinyl sulfones, which can be obtained by various methods of production, may often be contaminated by impurities or the like in the production process, and it has been difficult to use these organic layers directly as intermediates of drugs or other products. Thus, there has been a need for the isolation of crystalline powder of aryl vinyl sulfones with low purity, which can be obtained by the concentration of the said organic layers, and for the subsequent purification of the crystalline powder by recrystallization or other techniques. At that time, one must handle the crystalline powder of aryl vinyl sulfones, so that some problems will be caused on the working atmosphere, such as dusting, from the viewpoints of safety and health. Therefore, handling methods without handling crystalline powder have been required.
In particular, phenyl vinyl sulfone as a typical compound has been known to exhibit irritation (Aldrich Material Safety Data). Further, it has been reported that one should pay attention for safety to the handling of vinylsulfonyl group-containing compounds (Chemtech, November, 34 (1996)). Therefore, the development of methods without handling solids of aryl vinyl sulfones, by which aryl vinyl sulfones can be handled safely and healthily, has been desired.
The main object of the present invention is to provide a method for handling aryl vinyl sulfones safely and healthily without handling solids of aryl vinyl sulfones.
This object and the other objects, as well as the advantages, of the present invention are explained below.
The present inventors have studied processes of production as well as methods of transportation and storage without handling powder of aryl vinyl sulfones, thereby completing the present invention.
That is, the present invention provides a process for producing a purified aryl vinyl sulfone solution, characterized in that an aryl vinyl sulfone is crystallized from an organic solvent solution of a crude aryl vinyl sulfone to give a crystallization mixture, and a wet cake of the aryl vinyl sulfone obtained by the separation of the solution from the said mixture is dissolved in a solution-forming solvent selected from ethers of 4 to 8 carbon atoms, aromatic hydrocarbons of 6 to 10 carbon atoms, halogenated hydrocarbons of 1 to 6 carbon atoms, ketones of 3; to 8 carbon atoms, esters of 3 to 6 carbon atoms, and nitriles of 2 to 6 carbon atoms; methods of transportation and storage of a purified aryl vinyl sulfone as a solution; and use thereof.
First, the following explains a process for producing a purified aryl vinyl sulfone solution, characterized in that an aryl vinyl sulfone is crystallized from an organic solvent solution of a crude aryl vinyl sulfone to give a crystallization mixture, and a wet cake of the aryl vinyl sulfone obtained by the separation of the solution from the said mixture is dissolved in a solution-forming solvent selected from ethers of 4 to 8 carbon atoms, aromatic hydrocarbons of 6 to 10 carbon atoms, halogenated hydrocarbons of 1 to 6 carbon atoms, ketones of 3 to 8 carbon atoms, esters of 3 to 6 carbon atoms, and nitrites of 2 to 6 carbon atoms.
The organic solvent solution of a crude aryl vinyl sulfone as used in the present invention may include, for example, organic solvent solutions containing the crude aryl vinyl sulfone, which can be obtained by ordinary post-reaction treatments such as neutralization and water washing or by optional treatments such as desalting, from a reaction mixture obtained by the base treatment of a xcex2-haloethyl aryl sulfone, a xcex2-sulfate ethyl aryl sulfone, a xcex2-tosyloxyethyl aryl sulfone, a xcex2-mesyloxyethyl aryl sulfone or a xcex2-nitrate ethyl aryl sulfone, or from a reaction mixture obtained by the oxidation of a vinyl aryl sulfide.
More particularly, the crude aryl vinyl sulfone in the present invention may include those containing a compound obtained by the treatment of a compound of formula (I): 
wherein R1 and R2 are the same or different and are independently hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, or di(lower alkyl)amino, and L is a leaving group, with a base; or those containing a compound of formula (III): 
wherein R1 and R2 are as defined above, which is obtained by the oxidation of an aryl vinyl sulfide compound of formula (II): 
wherein R1 and R2 are as defined above.
The atoms or groups represented by R1 or R2 in formulas (I), (II), and (III) are defined as follows:
The halogen atom may include, for example, fluorine, chlorine, bromine, and iodine atoms;
The lower alkyl group may include, for example, straight chain or branched alkyl groups of 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, i-propyl, i-butyl, sec-butyl, t-butyl, neopentyl, and n-hexyl groups.
The lower alkoxy group may include, for example, straight chain or branched alkoxy groups of 1 to 6, carbon atoms, such as methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, i-propoxy, i-butoxy, sec-butoxy, t-butoxy, neo-pentoxy, and n-hexyloxy groups.
The lower alkylamino group refers to an amino group substituted with one lower alkyl group, in which the lower alkyl group may include the same groups as described above. Examples of the lower alkylamino group are methylamino, ethylamino, and t-butylamino groups. The di(lower alkyl)amino group refers to an amino group substituted with two lower alkyl groups, in which the lower alkyl groups may include the same groups as described above. Examples of the di(lower alkyl)amino group are dimethylamino, diethylamino, methylethylamino, and t-butylmethylamino groups.
The leaving group represented by L in formula (I) may include sulfate (OSO3H), nitrate (ONO2), and sulfonyloxy (e.g., tosyloxy, mesyloxy) groups, and halogen (chlorine, bromine, iodine) atoms.
Specific compounds of formula (I) may include compounds containing the leaving groups as described above, respectively, in the following aryl vinyl sulfones.
The base for use in the treatment of a compound of formula (I) may include inorganic or organic bases, or mixtures thereof The inorganic base may be hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide), or carbonates or bicarbonates (sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate), of alkali metals or alkaline earth metals.
The organic base may include mono-, di-, or trialkylamines (triethylamine) and pyridine compounds. For example, there can be mentioned the disclosures of [J. Org. Chem., 58, 4506 (1993), J. Chem. Soc., 1754 (1949)], [JP-A 10-251219], [German Patent No. 842,198 (1942)], [Bull. Korean Chem. Soc., 16, 670 (1995)], [JP-A 10-36337], and [JP-A 10-195039]; and methods in accordance with these disclosures.
The aryl vinyl sulfide of formula (II) may include aryl vinyl sulfide compounds corresponding to the aryl vinyl sulfones as described below.
Specific examples of the aryl vinyl sulfone are phenyl vinyl sulfone, (4-chlorophenyl) vinyl sulfone, (3,4-dichlorophenyl) vinyl sulfone, (4-bromophenyl) vinyl sulfone, (4-fluorophenyl) vinyl sulfone, (4-iodophenyl) vinyl sulfone, (4-methylphenyl) vinyl sulfone, (2,4-dimethylphenyl) vinyl sulfone, (4-ethylphenyl) vinyl sulfone, (4-i-butylphenyl) vinyl sulfone, (4-t-butylphenyl) vinyl sulfone, (4-methoxyphneyl) vinyl sulfone, (3,4-dimethoxyphenyl) vinyl sulfone, (4-t-butoxyphenyl) vinyl sulfone, (3-aminophenyl) vinyl sulfone, (3-methylaminophenyl) vinyl sulfone, (3-ethylaminophenyl) vinyl sulfone, (3-dimethylaminophenyl) vinyl sulfone, (3-dimethylaminophenyl) vinyl sulfone, and (3-nitrophenyl) vinyl sulfone.
The organic solvent used in the organic-solvent solution of the crude aryl vinyl sulfone, which is subjected to crystallization, is not particularly limited, but may include, for example, organic solvents selected from ethers of 4 to 8 carbons atoms, aromatic hydrocarbons of 6 to 10 carbon atoms, halogenated hydrocarbons of 1 to 6 carbon atoms, ketones of 3 to 8 carbon atoms, esters of 3 to 6 carbon atoms, and nitriles of 2 to 6 carbon atoms; and mixed solvents thereof
The ethers of 4 to 8 carbon atoms may include, for example, diethyl ether, methyl t-butyl ether, dimethoxyethane, diglyme, and dibutyl ether.
The aromatic hydrocarbons of 6 to 10 carbon atoms may include, for example, toluene, xylene, benzene, ethylbenzene, cumene, cymene, and t-butylbenzene.
The halogenated hydrocarbons of 1 to 6 carbon atoms (straight chain or optionally branched alkyl groups, aromatic hydrocarbons) may include, for example, dichloromethane, 1,2-diclhloroethane, chloroform, chlorobenzene, and carbon tetrachloride.
The ketones of 3 to 8 carbon atoms nay include, for example, acetone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, diethyl ketone, cyclopentanone, cyclohexanone, 2-heptanone, and ethyl amyl ketone.
The esters of 3 to 6 carbon atoms may include, for example, ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl formate, isopropyl formate, ethyl propionate, and 2-methoxyethyl acetate.
The nitriles of 2 to 6 carbon; atoms may include, for example, acetonitrile, propionitrile, butyronitrle, valeronitrile, and capronitrile.
Specific examples of the organic solvent solution of the crude aryl vinyl sulfone are as follows:
For example, solutions obtained by the reaction of a xcex2-haloethyl aryl sulfone with triethylamine in a hydrophobic aromatic hydrocarbon organic solvent such as benzene or tetrahydrofuran, or in an ether organic solvent, and the separation of resulting salts [J. Org. Chem., 58, 4506 (1993), J. Chem. Soc., 1754 (1949)];
Solutions obtained by the reaction of a xcex2-haloethyl aryl sulfone with an aqueous alkaline metal salt solution in the presence of an amine in a hydrophobic hydrocarbon organic solvent such as toluene, and the separation of an aqueous layer [JP-A 10-251219];
Solutions obtained by the reaction of an aryl sulfonyl ethanol with sulfuric acid in a halogenated hydrocarbon solvent such as dichloromethane, the treatment with a base such as an aqueous sodium hydroxide solution, and the separation of an aqueous layer [German Patent No. 842,198 (1942)];
Solutions obtained by the reaction of an aryl sulfonyl ethanol with methane sulfonyl chloride in a halogenated hydrocarbon solvent such as dichloromethane, the addition of triethylamine and reaction therewith, the addition of water and phase separation [Bull. Korean Chem. Soc., 16, 670 (1995)];
Solutions obtained by the reaction of an aryl sulfonyl ethanol with fuming nitric acid in a halogenated hydrocarbon solvent such as chloroform, the treatment with a base such as an aqueous sodium hydroxide solution, and the separation of an aqueous layer [JP-A 10-36337]; and
Solutions obtained by the treatment of an aryl sulfonyl ethanol with a chlorinating agent in a hydrophobic organic solvent such as toluene, base treatment, the addition of water and phase separation [JP-A 10-195039].
There can also be mentioned, for example, solutions obtained by the oxidation of an aryl vinyl sulfide with an aqueous hydrogen peroxide solution, the addition of an ether solvent such as diethyl ether, and water, and the separation of an aqueous layer [Org. Synth., 64, 157 (1985)].
For the organic solvent, preferably selected are those which make it easy to wash a wet cake after crystallization by combinations with a desired solution-forming solvent, or which they can easily be removed by making use of a difference in boiling point from the solution-forming solvent or the properties of exhibiting azeotropy therewith. They can be selected in the same manner as for the washing solvents as described below.
The method for crystallizing an aryl vinyl sulfone from a solution containing a crude aryl vinyl sulfone may include, for example, crystallization by cooling, crystallization by evaporation, and methods using an aryl vinyl sulfone-containing solution and a solvent in which the aryl vinyl sulfone is substantially insoluble (hereinafter referred to as a poor solvent). The aryl vinyl sulfone-containing solution may be subjected directly to crystallization treatment, or may be subjected to crystallization treatment after the removal by distillation of some of the solvent from the said solution.
For crystallization by cooling or crystallization by evaporation, the crystallization temperature, operational pressure, and other conditions may suitably be selected, depending on the concentration of an aryl vinyl sulfone in the crude aryl vinyl sulfone-containing solution, the solvent, and other factors.
When a crude aryl vinyl sulfone-containing organic solvent solution and a poor solvent are used, there may be used either a method in which the poor solvent is added to the said solution, or a method in which the said solution is added to the poor solvent, with the latter being preferred. The poor solvent may include, for example, aliphatic (straight chain or optionally branched, or cyclic) hydrocarbons of 5 to 10 carbon atoms, such as hexane, heptane, octane, cyclohexane, nonane, and decane. The amount of such a poor solvent to be used is usually at most 100 times greater by weight, preferably 0.5 to 50 times greater by weight, relative to the aryl vinyl sulfone contained in the said solution. The aryl vinyl sulfone crystals are usually deposited by mixing the aryl vinyl sulfone-containing organic solvent solution with the poor solvent. More aryl vinyl sulfone crystals may be deposited by further cooling.
The method for separating a solution from a crystallization mixture (slurry) containing aryl vinyl sulfone crystals, which is obtained by such a crystallization treatment, may include various methods usually used, such as transferring the slurry to a filtering module, followed by filtration, removing a supernatant from a crystallization vessel using a pump, and decanting a supernatant by tilting a crystallization vessel.
The solution formation of a wet cake of the aryl vinyl sulfone thus obtained can be carried out, for example, directly in the filtering module or crystallization vessel. Alternatively, it may also be achieved by transferring the wet cake from the filtering module to a subsequent dissolution tank and then adding a solution-forming solvent thereto.
The method of direct solution formation in a filtering module may include, for example, those by closing the liquid-drawing port of the filtering module, adding a solution-forming solvent into the filtering module, dissolving a wet aryl vinyl sulfone cake in the filtering module, and opening the liquid-drawing port to remove an aryl vinyl sulfone solution. The said solution formation treatment may be repeated, depending on the volume of the filtering module and the solubility of the aryl vinyl sulfone into the solution-forming solvent used. Further, after the drawing of a filtrate, the liquid-drawing line may be turned to another receiving vessel and kept open, in which state the solution-forming solvent is added into the filtering module and the wet aryl vinyl sulfone cake is formed into a solution, whereas the resulting solution is drawn.
When a wet cake of an aryl vinyl sulfone is transferred from the filtering module to another dissolution tank and formed into a solution by the addition of a solution-forming solvent, there can be mentioned, for example, a method in which the dissolution tank for the dissolution of the aryl vinyl sulfone has been previously connected to the cake-discharge port of the filtering module, and the filtered crystals are discharged from the cake-discharge port into the dissolution tank and formed into a solution by the addition of a dissolving solvent to the dissolution tank. The solution-forming solvent may have been previously charged into the dissolution tank. In the filtering module, some of the crystals sometimes remain undischarged, in which case the liquid-drawing port of the filtering module is closed, and a solution-forming solvent is charged into the filtering module, and the remaining crystals are dissolved, and the resulting solution is transferred from the cake-discharge port to the dissolution tank.
The addition of a solution-forming solvent may be carried out continuously or intermittently.
The solution-forming solvent may be an organic solvent selected from ethers of 4 to 8 carbon atoms, aromatic hydrocarbons of 6 to 10 carbon atoms, halogenated hydrocarbons of 1 to 6 carbon atoms, ketones of 3 to 8 carbon atoms, esters of 3 to 6 carbon atoms, and nitrile of 2 to 6 carbon atoms in the same manner as described above; or a mixed solvent thereof.
These organic solvents may suitably be selected, depending on, for example, the purposes of use of aryl vinyl sulfones. Among all these organic solvents are preferred ketones of 3 to 6 carbon atoms (particularly preferred are acetone, methyl ethyl ketone, methyl isobutyl ketone, or the like), which have high dissolubility for aryl vinyl sulfones; esters of 3 to 10 carbon atoms (particularly preferred is ethyl acetate or the like); and nitriles of 2 to 6 carbon atoms (particularly preferred is acetonitrile).
The amount of such a solution-forming solvent to be used may be any of the amounts enough to dissolve the crystals of aryl vinyl sulfones, and it may suitably be determined, depending on the solution-forming solvent used, the concentration of desired aryl :vinyl sulfone solutions, temperature, and other factors.
The temperature in the solution formation may be any of the temperatures at which aryl vinyl sulfones are dissolved in solution-forming solvents, and it may be usually 100xc2x0 C. or lower, preferably 0xc2x0 C. to 50xc2x0 C.
According to such a series of operations, a purified aryl vinyl sulfone solution can be obtained. When the introduction into the said solution of a crystallization solution adhering in a very small amount to the aryl vinyl sulfone crystals is to be reduced, the aryl vinyl sulfone crystals filtered can also be washed with a washing solvent to remove the adhering mother liquid, thereby attaining solvent replacement in advance of the solution formation. When the crystallization solvent has a lower boiling point than that of the solution-forming solvent or exhibits azeotropy with the solution-forming solvent, washing is not necessarily needed.
The washing solvent may be any of the solvents by which the mother liquid adhering to the crystals can be removed. When incorporation into a purified aryl vinyl sulfone solution finally obtained is to be avoided, the same solvent as the solution-forming solvent is used, or a solvent which exhibits azeotropy with the solution-forming solvent or which has a lower boiling point than that of the solution-forming solvent is used, and finally, any other solvent than the solution-forming solvent can also be removed by the partial concentration of an aryl vinyl sulfone solution.
When as such a washing solvent, a poor solvent in which aryl vinyl sulfones are substantially insoluble is used for washing, the amount of such a washing solvent to be used is not particularly limited. When any other solvent is used for washing, the amount of such a washing solvent to be used is preferably set at the lowest amount needed for the removal of a mother liquid adhering to the crystals, and it is used after cooled, if necessary.
As examples of the solvent exhibiting azeotropy, there can be mentioned, for example, hexane or ethyl acetate as the solvent exhibiting azeotropy with acetonitrile; diisopropyl ether and hexane as the solvent exhibiting azeotropy with acetone; ethyl acetate and hexane as the solvent exhibiting azeotropy with ethyl methyl ketone; acetone, ethyl acetate, diisopropyl ether, and hexane as the solvent exhibiting azeotropy with chloroform; and hexane exhibiting azeotropy with ethyl acetate; and it can be selected from the combinations of these solvents. In addition, the solvent exhibiting azeotropy with the above solutions-forming solvent or the solvent having a lower boiling point than that of the above solution-forming solvent can be selected and used from the solvents as disclosed in xe2x80x9cShinpan Youzai Pocket Book (edited by Yuki Gosei Kagaku Kyokai, Ohmsha, Ltd., pp. 62-66xe2x80x9d, Kagaku Binran, Kiso-hen II, 5th edition, Maruzen, pp. 147-149, (L. H. Horsley, xe2x80x9cAzeotropic Data-IIIxe2x80x9d, Advances in Chemistry Series, No. 116, American Chemical Society (1973), W. Malesinski, xe2x80x9cAzeotropyxe2x80x9d, Interscience Pub. (1965)).
Operations on and after the step of separating the wet cake of an aryl vinyl sulfone and the solution from the crystallization mixture solution are preferably carried out in a closed system. Of course the operation of crystallization may also be carried out in a closed system. By doing so, handling of an aryl vinyl sulfone in powder form can be avoided.
The aryl vinyl sulfone solution thus obtained can be concentrated or diluted with an additional solution-forming solvent to prepare an aryl vinyl sulfone solution of a prescribed concentration.
The concentration temperature in the concentration of an aryl vinyl sulfone solution may suitably be selected, depending on the solvent system, and it may be usually 100xc2x0 C. or lower, preferably 30-80xc2x0 C. The operational pressure may be determined, depending on the concentration temperature.
When the wet cake of an aryl vinyl sulfone obtained by the separation of the solution from the crystallization solution of the aryl vinyl sulfone is washed with a solvent exhibiting azeotropy with the solution-forming solvent, or when the crystallization solvent exhibiting azeotropy with the solution-forming solvent, the said solution can be concentrated to remove the washing solvent or crystallization solvent by azeotropy and then adjusted to a prescribed concentration.
When the wet cake of an aryl vinyl sulfone obtained by the separation of the wet aryl vinyl sulfone cake and the solution is washed with a solvent having a lower boiling point than that of the solution-forming solvent, or when a solvent having a lower boiling point than that of the solution-forming solvent is used as a crystallization solvent, the said solution can be concentrated to remove the low boiling point washing solvent or crystallization solvent and then adjusted to a prescribed concentration.
The concentration of an aryl vinyl sulfone in the aryl vinyl sulfone solution may suitably be selected, depending on the kind of organic solvent forming the said solution, and the range of temperature in the atmosphere for ordinary usage, storage, or transportation (in the range of ordinary temperature to about 50xc2x0 C.), and it may be usually 5-90% by weight, preferably 5-80% by weight. In such a range of concentration, the said solution has a low liquid viscosity and can usually be handled without any trouble.
In the process of the present invention, aryl vinyl sulfone solutions with 99% or higher ratios of aryl vinyl sulfones to the components except the solvent(s) in the analytical chromatogram (i.e., aryl vinyl sulfones with 99% or higher purity) can be obtained, and they can be used as intermediates of drugs or other products without any trouble.
The aryl vinyl sulfones in such solutions are sufficiently stable under the conditions and atmosphere in! which aryl vinyl sulfones are usually handled, such as for usage, storage, or transportation, and there will be no problems for their practical use.
The handling of purified aryl vinyl sulfones obtained by the production process of the present invention gives no trouble as compared with the handling work in powder form and makes it possible to keep at low levels the concentrations of aryl vinyl sulfones in the working atmosphere. Work can be done in the atmosphere hardly causing exposure to aryl vinyl sulfones.
In this manner, purified aryl vinyl sulfone solutions can be produced by the crystallization of aryl vinyl sulfones from aryl vinyl sulfone-containing solutions before purification, which can be obtained by various reactions; separation of solutions from the crystallization mixtures to obtain wet cakes of the aryl vinyl sulfones; and dissolution of these cakes in solution-forming solvents.
According to the process of the present invention, purified aryl vinyl sulfone solutions can be obtained, without no trouble, such as dusting, from the viewpoint of working atmosphere because of an absence of handling in solid form, and under an atmosphere in which the concentrations of aryl vinyl sulfones in the air are lowered over a working area for the production of aryl vinyl sulfones and handing the same. Further, the aryl vinyl sulfone solutions obtained are easy to handle, suitable for storage and also for transportation. They further have good aryl vinyl sulfone purity and can be used as synthetic materials of drugs or other products without any trouble.